SBDS is a ribosomal maturation factor essential for 80S ribosome assembly and translation competence. 1 SBDS functions together with EFL1 to trigger GTP-dependent release of eIF6 from 60S pre-ribosomes in the cytoplasm, enabling ribosome activation and facilitating eIF6 recycling to the nucleus for 60S rRNA processing and nuclear export. 1 This mechanism is critical for maintaining normal protein synthesis levels. 2 Pathologically, SBDS mutations cause Shwachman-Diamond syndrome (SDS), an autosomal recessive ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure with neutropenia, and severe predisposition to myeloid malignancies. 1 Approximately 90% of clinical SDS cases carry SBDS mutations. 2 The disease results from impaired ribosomal maturation and inability to evict eIF6 from the 60S subunit. 1 Clinically, SDS patients face extremely poor outcomes when developing myeloid malignancies due to high treatment-related toxicities and refractory disease. 1 Recent molecular advances reveal that somatic EIF6 inactivation can provide ribosomal rescue, while biallelic TP53 mutations increase leukemogenic potential. 1 Single-cell DNA sequencing can detect premalignant TP53-mutated clones before clinical diagnosis, enabling earlier hematopoietic stem cell transplantation when most effective. 1